Foghorn Therapeutics Inc. · NASDAQ:FHTX
Foghorn Therapeutics — Technical Presentation (June 2021)
110 slides from Foghorn Therapeutics's technical presentation, Jun 15, 2021
Slide 1: Targeting the Chromatin Regulatory System
Exhibit 99.1 » Targeting the Chromatin Regulatory System Broadening the Impact of Precision Medicines for Oncology and Other Diseases FCGHORN THERAPEUTICS Research & Development Webinar Un June 15, 2021
Slide 2: Webinar agenda
9:00 -9:10 a.m. 9:10 -9:25 a.m. 9:25 -9:45 a.m. 9:45 -10:05 a.m. 10:05 -10:20 a.m. 10:20 -10:30 a.m. 10:30 -10:45 a.m. 10:45 -11 :00 a.m. FOGHORN' THlaRAPlaVTICS Welcome and Introduction Adrian Gottschalk, P resident and CEO, Foghorn Therapeutics Chromatin Regulatory System -Disease Relevance Cigall
Slide 3: Welcome and Introduction
FOGHORN THERAPEUTICS Welcome and Introduction
Slide 4: Forward-Looking Statements
Forward-Looking Statements This presentation contains forward-looking statements. All statements other than statements of historical facts contained in this presentation are forward-looking statements. In some cases, you can identify forward-looking statements by terms such as “may,” “will,” “should
Slide 5: The Foghorn Commitment
The Foghorn Commitment C OUR PLEDGE At Foghorn, we pledge to partner with patients as we work to discover and develop new, effective therapies for a wide spectrum of diseases, including many types of cancer. Every member of our team is committed to making a difference in the lives of others. FCGHORN
Slide 6: Targeting the Chromatin Regulatory System
Targeting the Chromatin Regulatory System Broadening the Impact of Precision Medicines for Oncology and Other Diseases: ( July: Collaboration agreement Global integrated with Merck to develop a biotech company from transcription factor disruptor discovery to Development of Gene 2020: Total capital f
Slide 7: Dysregulation of the Chromatin Regulatory System Implicated in up to 50% of All Cancers
Dysregulation of the Chromatin Regulatory System Has Been Implicated in up to 50% of All Cancers 50% 2.5M $400+ of All Cancers People billion Based on exome sequencing, Potential impact for Foghorn’s 2030 global oncology the chromatin regulatory pipeline of precision oncology market opportunity syst
Slide 8: First Two Programs in the Clinic, Broad Pipeline Advancing
First Two Programs in the Clinic, Broad Pipeline Advancing Precision Oncology / Breadth and Depth Program / Target Modality Discovery IND-enabling Phase 1 Phase 2 Phase 3 Global Rights FHD-286 Early Clinical Data (Q4 2021) pleas Er hibit (BRG1/ BRM) nzyme inhibitor Early Clinical Data (Q4 2021) Soe
Slide 9: Webinar agenda
9:00 -9:10 a.m. 9:10 -9:25 a.m. 9:25 -9:45 a.m. 9:45 -10:05 a.m. 10:05 -10:20 a.m. 10:20 -10:30 a.m. 10:30 -10:45 a.m. 10:45 -11 :00 a.m. FOGHORN' THlaRAPlaVTICS Welcome and Introduction Adrian Gottschalk, P resident and CEO, Foghorn Therapeutics Chromatin Regulatory System -Disease Relevance Cigall
Slide 10: Chromatin Regulatory System — Disease Relevance
FOGHORN THERAPEUTICS Chromatin Regulatory System — Disease Relevance
Slide 11: Targeting chromatin regulatory system perturbations
Targeting,chromatin,regulatory system perturbations i oot human disease re : @ >» Dana-Farber - q Cancer Institute mae ae ea HARVARD A , Fe '» & MEDICAL SCHOOL e, OY = BROAD ae INSTITUTE Cigall Kadoch, Ph.D. Dana- Farber Cancer Institute Harvard Medical School Broad Institute
Slide 12: Chromatin architecture and accessibility govern gene expression
Chromatin architecture and accessibility govern gene.exp V. Attoulian,
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Slide 15: Chromatin architecture and accessibility govern gene expression
Shromatin architecture and accessibility govern gene
Slide 16: The chromatin regulatory system
The chromatin regulatory system POR OLARERS ROK & a
Slide 17: The chromatin regulatory system
The chromatin regulatory system @ DNA modification ©) Histone modification [ ) Chromatin remodeling complexes
Slide 18: The chromatin regulatory system
The chromatin regulatory system @ DNA modification ©) Histone modification [ ) Chromatin remodeling complexes Nucleus
Slide 19: The chromatin regulatory system
The chromatin regulatory system DNA modification . Hist dificati Defects in the control of chromatin Istone MOGMCauon structure are a major @ Chromatin remodeling complexes cause of human disease Nucleus Development Response to Differentiation Lineage stimuli commitment and restriction r - jose “ier
Slide 20: Human genetic studies unlock new biology
Human genetic studies unlock new biology 3 2 TL Gl = Cancer MahGte akKases Neurodevelopment disorders I diti oy’ é ” “é 7 Ci a L Heart development and disease rz St eK a Others . «eo a 3 i¢ »% Artist credit: Sonya Parpart-Li ©
Slide 21: Cancer mutations span multiple cellular pathways
Cancer mutations span multiple cellular pathways 30+ Cancer Types >10,000 tumor samples sequenced ~300 driver genes >3,400 putative missense driver mutations Apoptosis — | f ies TOR signaling} | | NOTCH signaling Epigenetics DNA modifiers esi I T NFKB signaling Chromatin other ls Metabolism: | wey S
Slide 22: Chromatin regulatory system disruptions are extensive
Cellular Pathways Chromatin regulatory system disruptions are extensive 30+ Cancer Types >10,000 tumor samples sequenced ~300 driver genes >3,400 putative missense driver mutations Epigenetics DNA modifiers | Chromatin other Chromatin histone modifiers | Histone modification [ [ EI i! ==! =I a UE Ey
Slide 23: Chromatin regulatory system disruptions are extensive
Cellular Pathways Chromatin regulatory system disruptions are extensive 30+ Cancer Types >10,000 tumor samples sequenced ~300 driver genes >3,400 putative missense driver mutations Epigenetics DNA modifiers | __ I i Chromatin other I = = =I a Chromatin histone modiiers [| rr le |) Histone modificati
Slide 24: Mutational landscape of mSWI/SNF genes in human cancer
An example: mutational landscape of mSWI/SNF genes in human cancer ~20+% of human cancers Drivers of rare cancers (many 90-100% of cases) mSWI/SNF gene og -ARIDIA - SMARCA2 - SMARCC2 - ACTB - BRD7 = GLTSCRIL - SMARCCL 0.08 ° S 8 é moe g .3) .3) Be: 3 Ss = = sas $ 5 SMARCB1 i] a = a8 ap. uanceT = = G
Slide 25: Mammalian SWI/SNF complexes: chromatin remodeling machines
Mammalian SWI/SNF complexes: chromatin remodeling machines ARIDIA ARID1B ARID2 SMARCA4 SMARCA2 SMARCC1 SMARCC2 SMARCD1 SMARCD2 SMARCD3 SMARCE1 SMARCB1 PBRM1 DPF1 DPF2 DPF3 PHF10 BRD7 BRD? $S18 $S18L1 ACTL6A ACTL6B ACTB GLTSCR1 GLTSCRIL BCL7A BCL7B BCL7C mSWI/SNF (BAF) complex Three distinct final fo
Slide 26: Mammalian SWI/SNF complexes: chromatin remodeling machines
Mammalian SWI/SNF complexes: chromatin remodeling machines
Slide 27: mSWI/SNF family complexes: cBAF, PBAF, and ncBAF types
mSWI/SNF family complexes: cBAF, PBAF, and ncBAF types SMARCA4/2] ARIDIA/B = Stand SMagoctys SMARCD¢f Mashtalir et al., Ce// 2018 Michel et al., Nat Cel! Bio! 2018
Slide 28: mSWI/SNF: diverse assemblies yield diverse opportunities for targeting
mSWI/SNF: diverse assemblies yield diverse opportunities for targeting BAF ARID1/B vane DPF2 ‘ sce acidic patch Biochemical syazce: composition, 3D \) structure, NCP interactions or” “ener SMaARCCH! Suwanee ¢ ) smarcoie ‘SMARCEI ARID2 PBRM1 PHF10 Nucleoseme acidic patch smaRcat =. PERM BROT PBAF 1.4
Slide 29: Compositional and functional diversity of mSWI/SNF complexes
Compositional and functional diversity of MSWI/SNF complexes cBAF ncBAF ARID1/B WEF KiB ARID2 — pparF BRD9 DPF2 PBRM1 4.41 Mpa @LtscriL °87Ma oe SaRCAa2 PHF10 ° SMARCAAI2 --" piPase suiunts “SMARCB1 ‘ATPase subunits +" ATPase subunits “SMARCE! epee Nutcase ‘leeeeae - GLTSCR1 instead 7 , - ee if ARID
Slide 30: Multi-subunit/multi-cancer studies potentiate identification of new mechanisms
Multi-subunit/multi-cancer studies potentiate identification of new mechanisms SMARCA4/ Non-small cell lung cancer (12% SMARCA2 sccoHT (~100%) . SA4-deficient thoracic sarcomas (~100%) Pan et al., Nature Genetics 2019 SMARCB1 Malignant rhabdoid tumor (598%) Atypical teratoid/rhabdoid tumor (298%). E
Slide 31: Multi-subunit/multi-cancer studies potentiate identification of new mechanisms
Multi-subunit/multi-cancer studies potentiate identification of new mechanisms Biochemical assembly and modularity Mashtalir et al., Cell 2018 SMARCB1 Malignant rhabdoid tumor (>98%) oe Atypical teratoid/rhabdoid tumor (>98%) Epithelial sarcoma (>90%) Pediatric chordoma (50%) Valencia et al., Cell,
Slide 32: Multi-subunit/multi-cancer studies potentiate identification of new mechanisms
Multi-subunit/multi-cancer studies potentiate identification of new mechanisms Biochemical assembly and modularity Mashtalir et al., Cell 2018 SMARCA4I cccont (~100%) SMARCAZ spq-deficient thoracic sarcomas (~100%) Non-small cell lung cancer (12%) Pan et al., SMARCB1 Malignant rhabdoid tumor (>98%)
Slide 33: Much more to do: chromatin remodeler complex mutations are widespread
Much more to do: chromatin remodeler complex mutations are widespread [yer encning . ; . . cBAF Non-truncating @ NDD-subunit specific Neurodevelopmental Disorder (NDD) @ NDD-mapped from paralog Mutations ~ gnomAD (general population) SMARCA2I4 re hy 8 3 = = = ‘= DNA-binding domains cc ae a Histone r
Slide 34: Recurrent cancer-associated mutations highlight broad opportunity for precision medicine
Recurrent cancer-associated mutations highlight broad opportunity for precision medicine Pan-Cancer Mutations (COSMIC) mapped on to Missense mutations in SMARCA2/4 endogenous cBAF complex model RIS18PIG (6) R521WILIP (7) ‘ R1356W/Q (5) x — ae) Structural classification of BAF complex cancer-associat
Slide 35: Chromatin remodeling complexes are major determinants of chromatin architecture
Chromatin remodeling complexes are major determinants of chromatin architecture and gene expression Tissue-specific context nee ¢ Actionable dependencies arise from: Paralog deletions/mutations - SMARCA4/SMARCA2, ARID1A/B, others Shifted assembly and activities of complexes - cBAF-perturbed cancers—
Slide 36: Gene Traffic Control Platform
FOGHORN THERAPEUTICS Gene Traffic Control Platform
Slide 37: Dependencies within the Chromatin Regulatory System
Dependencies within the Chromatin Regulatory System Integrated, Scalable, Efficient Repeatable Paradigm Our Gene Traffic Control Platform Makes It Possible to Understand and Drug Genetic ( =» =» Target Identification Production of Discovery and Optimization Translation to Clinic and & Validation Chr
Slide 38: Rationale for BAF Targets: BRM/BRG1 Threads Through Entire Complex
Rational for BAF Targets: BRM/BRG1 Threads Through Entire Complex © Allostery! ' BAF155/170 ARIDIA/B ——iiiaal papeiion BRM/BRG1 HSA BAF53A B-actin FOGHORN Yeast Swi/Snf cryo EM structure THERAPEUTICS
Slide 39: Platform is Powered by Ability to Produce Components at Scale
Platform is Powered by Ability to Produce Components at Scale Drives Drug Discovery Pipeline with Cutting Edge Technology Production of Chromatin Regulatory System Components FOGHORN THERAPEUTICS Features Surface Mapping Assembly Affinity Screening and Validation HTS Biophysics/ SPR Benefits Charact
Slide 40: Protein Degradation — Evolving Therapeutic Modality
Protein Degradation — Evolving Therapeutic Modality NH, 7 ¢ Degrader q NH, ee Ternary GC complex Target Protein Catalytic process | NH Peptide fragments Proteasome Polyubiquitination FOGHORN THERAPEUTICS
Slide 41: Heterobifunctional Degrader Platform
Heterobifunctional Degrader Platform Foghorn Pursuing >8 Targeted Protein Degraders + Optimal E3 ligase target pairing Bioinformatics + Proteomics + Proprietary chromatin remodeling assays + Protein degradation kinetics + Proprietary library of drug-like linkers and E3 ligase binders Chemical Toolbo
Slide 42: Targeting ARID1A Mutated Cancers: ARID1B Protein Degrader
Targeting ARID1A Mutated Cancers: ARID1B Protein Degrader Advantaged by Gene Traffic Control Platform and Protein Degrader Capabilities Gene Traffic Control Platform Protein Degrader Capabilities » Platform produces BAF complexes and subcomplexes containing either + Utilize protein degrader toolbox
Slide 43: First Two Programs in the Clinic, Broad Pipeline Advancing
First Two Programs in the Clinic, Broad Pipeline Advancing Precision Oncology / Breadth and Depth Program / Target Modality Discovery IND-enabling Phase 1 Phase 2 Phase 3 Global Rights FHD-286 Early Clinical Data (Q4 2021) pleas (BRG1/ BRM) Enzyme inhibitor Early Clinical Data (Q4 2021) Soe FHD-609
Slide 44: Selective BRM Modulators for BRG1 Mutated Cancers
FOGHORN THERAPEUTICS Selective BRM Modulators for BRG1 Mutated Cancers matic Inhibitor and Protein Degrader Programs
Slide 45: BRG1 Mutations Create a Genetic Dependency on BRM
BRG1 Mutations Create a Genetic Dependency on BRM Selective BRM Modulators Overview BRM Target / eae Approach Enzymatic inhibitor Targeted protein degrader BRG1 mutated cancers Apt (e.g., NSCLC), 30+ Indication cancers with BRG1 mutations Mutation / Aberration BRGI Stage Pre-clinical New Patients Im
Slide 46: BRG1 Mutated in ~5% of All Tumors
BRG1 Mutated in ~5% of All Tumors Broad Addressable Patient Population 0% 5% 10% 15% Cancer of Unknown Primary Skin Cancer, Non-Melanoma Non-Small Cell Lung Cancer Bladder Cancer Endometrial Cancer Colorectal Cancer Melanoma Cervical Cancer Thymic Tumor Esophagogastric Cancer Peripheral Nervous Syst
Slide 47: In Vivo Target Engagement With ~20X Selective BRM Inhibitor
In Vivo Target Engagement With ~20X Selective BRM Selective Inhibitor © PD Modulation in the H1299 BRG1-Null NSCLC PD Model Establishing a Direct Exposure-Response Relationship Targeting BRM: KRT80 PD Biomarker 10000 1000 100 KRT80 relative level (qu/6u) yd ewse|d 10 1 Q =o go ao oo oo a a a = Ss >
Slide 48: BRM Selective Inhibitor In vivo Efficacy
BRM Selective Inhibitor In vivo Efficacy Demonstrates PK/PD and In vivo Efficacy ina BRG1 Mutant Lung CDX Model A549-BRG1 Mutant NSCLC Model Body Weight aad Fv & E 100: S < A % £ 1000 * wd > ; 1 eat 10 20 30 40 £ days after implantation 2 g Plasma Exposure ‘ J = £ 500 z Z rs 1000. 8 £ 400. Pi “== BR
Slide 49: Scaffolds With Enzymatic Selectivity > 100X
Scaffolds With Enzymatic Selectivity > 100X BRG1 vs BRM ATPase activity [Stafiold_ SCAFFOLD NA @erZy 34 | eign selective sub-series ens Equations [=1% ~100x ~305 BRG1 IC50 (UM) Scaffold SCAFFOLD EPZM Scaffold SCAFFOLD NVS 0.003 001 0.03 O14 BRM IC50 (uM) 0.001 FOGHORN THERAPEUTICS
Slide 50: Strong Correlation from Enzyme to Cellular Reporter Assays
Strong Correlation from Enzyme to Cellular Reporter Assays 3 3. m 4 =: 5 3 oe Sa wo 8 8 3 @ © 6 a = FE 00s oss = < & on 2 iw a oO le ° 008 wai wet 0.001 oot 0.03 on bid 1 * " 0.003 oot 0.03 on 03 1 3 10 BRM Cellular IC50 (uM) BRG1 Cellular IC50 (uM) FOGHORN THERAPEUTICS
Slide 51: Advancing BRM Selective Degraders
Advancing BRM Selective Degraders Achieving Complete BRM Degradation BRM/BRG1 HiBit Data A549 Ten-Day Proliferation Assay 100 ss = FHT-BRMd #75 ‘es § 50 100: 3 25 2 50: = ® oh BG 0.01 0.1 1 10 100 1E3 0.01 90.1 1 10 50: Cone (uM) concentration (uM) Degraders cause time- and dose-dependent BRM degrad
Slide 52: Target Hopping to Related Helicase Targets
FOGHORN THERAPEUTICS Target Hopping to Related Helicase Targets
Slide 53: ATP Dependent Helicases
ATP Dependent Helicases Potential to Broaden Pipeline and Further Validate Platform Breadth FOGHORN THERAPEUTICS
Slide 54: Target Hopping to Related Helicase Targets
Target Hopping to Related Helicase Targets lass e (@ sence) @ seies2 ia e 100 A e 30 e ' i] 10 5 — 3 Be, ae o > * =. ° a Fa e ° ° e ° Dos Phe ‘2 3 ene o4 Os o , oe * e ° ° ° 0.03. oe ‘ ; 001 ee | ba e 0.003 ° ‘ 1 03 1 3 70 30 100 FOGHORN Helicase 1C50 um THERAPEUTICS
Slide 55: Potency Improved to Sub nM
Potency Improved to Sub 100 nM Target Hopping Validation by Medicinal _ Hits ASMS and DMF Chemistry IC50 = 70 nM 125 =| 100 % activity (%) s 0.01 01 1 10 100 Temperature, Celsius Concentration (uM) FOGHORN THERAPEUTICS
Slide 56: Novel Approach to Targeting Transcription Factors
FOGHORN THERAPEUTICS Novel Approach to Targeting Transcription Factors Disrupting Transcription Factor —- Chromatin Remodeling Complex Interactions
Slide 57: A New Approach to Drugging Transcription Factors
A New Approach to Drugging Transcription Factors Enabled by Proprietary Ability to Purify and Synthesize Chromatin Regulatory System Components », TFs are compelling drug targets... Foghoris kocus Highly involved in gene expression * Implicated in range of cancers and other Potential diseases drugga
Slide 58: Transcription Factor-Chromatin Remodeling Complex Interactions
Transcription Factor-Chromatin Remodeling Complex Interactions Unique Insights in Where and How Transcription Factors Bind TF #4 KD = 21 nM KD = 125 nM KD = 94nM KD = 351 nM 400- 250- 350- 2 200- 300: soo 250 40 200- 3 2 3 2 200 2 oo 2 iso ii i 400 0 o- &, 0- 0- == ta eeooeD CD ee z a = 0.01 04 1 10
Slide 59: SPI1: Transcription Factor SPI1 Dependency in AML
SPI1: Transcription Factor SPI1 Dependency in AML SPI1 inhibition selectively inhibits the growth of AML cell lines | mee 224 cit tine | Dependency Treshold of 0.3 Aberrant SPI1 overexpression BAF es 5] Remodeling ZO Cancer Cell Lines Machine 4 sPi Dependency Score CRISPR Screening data by Achilles
Slide 60: ATAC-seq Shows SPI1 Regulatory Elements are BAF Dependent
ATAC-seq Shows SPI1 Regulatory Elements are BAF Dependent Dual ATPase Inhibitor => -66-0-0-0-000-66- ATAC-Seq measures open regions of genome z har he fe ee 2 " BGAGGAAGTS See oe = ~[NSACGAAGT bear fr fms > | BAASESGAMETE SasaRT =f SRGAARTGAAAS eee ft [ oa z Dual ATPase ' |ASSAGGAAGE epeor fe femal
Slide 61: Full BAF Mapping Identifies Key Interactions With SPI1
Full BAF Mapping Identifies Key Interactions With SPI1 TR-FRET Based Screening Assays Constructed 7 ITC TR-FRET as a a oe a! i fk l(a 300000 2 = 92- 200000: . 2 a 3 3 “ 100000 $ H a a a er Time (min 0.1 1 10 100 1000 Model: One Set of Sites {Cell] (M) = 30.0e-6 694 # 1.362 Control curves have key in
Slide 62: Highly Scalable Approach and Significant Unmet Medical Need
Highly Scalable Approach and Significant Unmet Medical Need Potential to Drug > 100 TFs Associated with BAF » >100 TFs estimated associated with BAF » Foghorn pursuing multiple TFs in parallel » Approach highly scalable and potential broad application — other chromatin remodeling complexes and other
Slide 63: FHD-286: Clinical Entry Point - AML and Uveal Melanoma
FOGHORN THERAPEUTICS FHD-286: Clinical Entry Point - AML and Uveal Melanoma
Slide 64: FHD-286 Targets Abnormal Dependencies on BAF in Cancer
FHD-286 Targets Abnormal Dependencies on BAF in Cancer » BRG1/BRM ATPase BAF Chromatin Remodeling Complex Target/ Approach - Small molecule, allosteric, oral enzymatic inhibitor * Acute myelogenous leukemia (AML) Indications: » Uveal melanoma * Indication expansion work ongoing in multiple solid tum
Slide 65: AML Dependency on BRG1 / Lineage Dependent TF Interactions
AML & Dependency on BRG1 / Lineage Dependent TF Interactions © Treatment with FHD-286 o So AML blasts stuck in BAF / TF dependent proliferative phase poset Gines phenotype ! Apoptosis agen Disease State Cancerous blast cells rely on BRG1 containing BAF / TF activity BAF — TF Activity BAF — TF Activi
Slide 66: AML Dependent on BRG1 / Lineage TF Interaction
AML Dependent on BRG1 / Lineage TF Interaction BRG1 Inhibition Leads to : : SPI1 (PU.1) / BAF Dependency Loss of SPI1 (PU.1) Four TF’s Associated With 70% of AML Occupancy on Chromatin SsPIt ML cel baa ied mm AML cell line 10 (P os — SPI1 ChiPseq 35 00 —— — 30 H — i Dependency Teal of 2:3 ES : a Ss
Slide 67: erved by Bioluminescence
\ [ ‘ erved by Bioluminescence FHD-286 (batten Vehicle wm ww 1.5 mg/kg, BID " ‘ A i 4 (5on / 8off) x3 y FHD-286 ff Sorafenib 1.5 mg/kg 15 mg/kg, QDx28 QDx14 FOGHORN
Slide 68: FHD-286 Survival Advantage in Disseminated AML Model
FHD-286 Survival Advantage in Disseminated AML Model Vehicle FHD-286 1.5 mpk, BID (Son/8off)x3 FHD-286 1.5 mpk, QDx28 Sorafenib 15 mg/kg, QDx14 100 FREE Percent survival 3 0 10 20 30 40 Days post implant FOGHORN THERAPEUTICS
Slide 69: FHD-286 Shows Broad Efficacy Across AML Patient Derived Samples
FHD-286 Shows Broad Efficacy Across AML Patient Derived Samples Pieris Pace eaves Y Disease Status] 1690AML1 AML Secondary 1695AML1 AMLIMDS Secondary 1696AML1 AML Secondary 1701AML1 AML Secondary 1893AML1 AML RR 1899AML1 AML RR 1990pAML1 AML RIR 1991pAML1 AML de novo 2041AML1 N/A de novo 2043pAML1 A
Slide 70: FHD-286 Shows Effect Across a Range of Mutations in AML Samples
FHD-286 Shows Effect Across a Range of Mutations in AML Patient-Derived Samples 480 @ pnuT34 400 @ FLT3 © 10H @ ipH2 500. @ KT @ nF @ nem @ nras D RUNX1 @ ter @ tPs3 IC50 (nM) Patient Samples FOGHORN THERAPEUTICS
Slide 71: Potential PD Marker: AML TFs and Gene Signatures
Potential PD Marker: AML TFs and Gene Signatures BAF Regulates SPI1, A Key Transcription Factor in AML Subsets SPI (PU.1) Target Genes Menin-MLL Targets FHD-286 downregulates SPI1 protein and downstream SPI1 target genes 2,0%105- ‘SPI 1508 E sono! sono ° 1 on unstained 77 100nM unstained FOGHORN THE
Slide 72: Uveal Melanoma
Uveal Melanoma Disease Overview Primary Disease: * ~1,500 cases diagnosed each year, US » Age at diagnosis: early 60s-median, 70s-peak * ~30% asymptomatic — Lesion found on routine eye exam » Mild symptoms such as blurry vision in one eye * 95+% are primary disease at diagnosis Metastatic Disease: *
Slide 73: Metastatic Uveal Melanoma
Metastatic Uveal Melanoma Disease Overview * Treatment: No approved treatments — Liver Directed: Chemoembolization, radio- ablation, immunotherapy — Systemic: Ipilimumab + nivolumab, dacarbazine, temozolomide High Unmet Need FOGHORN THERAPEUTICS Overall survival (%) Number at risk Time (years) CHT 2
Slide 74: Therapeutic Rationale for Uveal Melanoma: TF and BAF Complex Interaction
and BAF Complex Interaction Inhibiting BRG1/BRM to Shut Down the Abnormal TF Interaction with the BAF Complex Therapeutic Rationale for Uveal Melanoma: Dependency on MITF / SOX10 TF’s ( Biology Validation of Dependency and Approach Over 85% of uveal melanoma cancers <i MITF ChiPseq have GNAQ or GNA1
Slide 75: Dual BRG1/BRM Inhibition
Dual BRG1/BRM Inhibition Disrupts the SOX10-MITF Transcriptional Axis in Uveal Melanoma A * B Cc u sient ia sania r 1 se, cca | Mia os totes $10. { a f t in } | ia Zz if Bo a | ~ 4 Ee | | bbl! mnt ‘1. A 26. = ms c= = i 5 q | ; = — Ba en a Be = a 3 a = 'SOX10 enhancer element 2 ‘SOX10- 12 lp E Ee Par
Slide 76: Melanoma CDX Models at Tolerated Doses
Melanoma CDX Models at Tolerated Doses FHD-286 was Associated with Dose-Dependent Tumor Regression in Uveal C MP-46 uveal melanoma azo, | Umer Volume +66, Body Weight CDX model a SI E 9004 3 110 » Dose-dependent tumor growth £ é inhibition 3g 6004 = 100 s S 5 » Well tolerated — 3004 = 90. e 8 1 ® 80
Slide 77: BRG1/BRM Inhibition Induces Apoptosis in UM Cell lines
BRG1/BRM Inhibition Induces Apoptosis in UM Cell lines 92-1 MP41 12000 7000 12000 6000 in = 10000 5000 oS @ & 8000 4000 oO 8a BE sooo 3000 5a [s} D t000 2000 2000 4000 ° = ° o 0 20 0 0 5 6 7 8 0 20 40 ey 20 Se Se sk ai See FHT-BRG1/BRMi (uM) Hours post-treatment e031 2016 e008 e004 —e-oms0 Significa
Slide 78: FHD-286 Clinical Development Plan
FHD-286 Clinical Development Plan Two Parallel Phase 1 Studies Activated ICAL PLAN AML & Uveal Melanoma FIH Phase 1 Studies Relapsed / Refractory AML & MDS Potential for entry into definitive efficacy trials in AML Metastatic Uveal Melanoma Pe Expansion i i cohorts in AML. ; Trial Designs UM and : P
Slide 79: Indication Expansion Opportunities for FHD-286
Indication Expansion Opportunities for FHD-286 0; en@eeonecdowne e@ nature e COMMUNICATIONS ARTICLE (Gomes) Cen Role of specialized composition of SWI/SNF e complexes in prostate cancer lineage plasticity & e Joanna Cyrta et at* CO@ © ce & @ SCIENTIFIC REPORTS ratureresearch a FHT-BRG1/BRMi IC50 (nM
Slide 80: Acute Myeloid Leukemia in 2021
Memorial Sloan Kettering Cancer Center 1884 Acute Myeloid Leukemia in 2021 Eytan M. Stein, MD Director, Program for Drug Development in Leukemia Leukemia Service Memorial Sloan Kettering Cancer Center NewYork, New York
Slide 81: Acute Myeloid Leukemia
Acute Myeloid Leukemia Memorial Sloan Kettering =, Cancer Center
Slide 82: AML is Complicated
AML is Complicated "RUNX1 40% [MLLPTD "25% ‘ASXL1 20% | DNMT3A 20% Noivers FLTSITD 35% SASF2"20% | STAGZ 15% | HE om 1(15;17)(q22;921); PML-RARA [FETS TKD “15% NRAS “15% | FLTSITD 15% |[ONMT3A 70%] 3% Wits : 5 TET215% | BCOR 10% ; ; U2AF1 10% | PHF 10% woanyaaaz2.ty RUNX1-RUNXATC ZASR2°5% | SF3B1~10
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Foghorn Therapeutics — Technical Presentation (June 2021) on 6ix